PURPOSE: Type 2 diabetes mellitus (T2DM) is a recognized risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). Mitochondrial dysfunction caused by disturbance of calcium (Ca2+) homeostasis might be a pathophysiological link between T2DM and AD. In the present study, we investigated the effects of aerobic training on the regulation of mitochondrial calcium homeostasis, mitochondrial function (O<sub>2</sub> respiration), and apoptosis in the hippocampus of T2DM rats.METHODS:Thirty male Otsuka Long-Evans Tokushima Fatty rats were divided into three groups: control group (CON, n=10), diabetes control group (DM, n=10), and diabetes+aerobic exercise group (DM+EXE, n=10). The rats in the exercise group were forced to run on a treadmill for 30 min, three times a week for 8 weeks.RESULTS:The DM group showed significantly increased mitochondrial calcium uniporter (MCU) protein and apoptosis-related factors such as Bax and caspase-3 and decreased mitochondrial O<sub>2</sub> respiration when compared with the CON group. However, the hippocampus of rats in the DM+EXE group exhibited a significant decrease in MCU, Bax, and caspase-3 levels and an increase in Bcl-2 and mitochondrial O<sub>2</sub> respiration when compared with the DM group.CONCLUSIONS:These results suggest that regular aerobic exercise alleviates mitochondrial dysfunction and apoptosis by modulating MCU, which is involved in mitochondrial Ca2+ homeostasis in the early stages of T2DM. This might be a potent strategy to prevent neurodegenerative diseases.